The natural intervertebral disc contains a jelly-like nucleus pulposus surrounded by a fibrous annulus fibrosus. Under an axial load, the nucleus pulposus compresses and radially transfers that load to the annulus fibrosus. The laminated nature of the annulus fibrosus provides it with a high tensile strength and so allows it to expand radially in response to this transferred load.
In a healthy intervertebral disc, cells within the nucleus pulposus produce an extracellular matrix (ECM) containing a high percentage of proteoglycans. These proteoglycans contain sulfated functional groups that retain water, thereby providing the nucleus pulposus with its cushioning qualities. These nucleus pulposus cells may also secrete small amounts of cytokines as well as matrix metalloproteinases (MMPs). The cytokines help regulate the metabolism of the nucleus pulposus cells.
In some instances of disc degeneration disease (DDD), gradual degeneration of the intervertebral disc is caused by mechanical instabilities in other portions of the spine. In these instances, increased or unconventional loads and pressures on the nucleus pulposus cause the cells to emit larger than normal amounts of the above-mentioned cytokines. In other instances of DDD, genetic factors or apoptosis can also cause the cells within the nucleus pulposus to emit toxic amounts of these cytokines and MMPs. In some instances, the pumping action of the disc may malfunction (due to, for example, a decrease in the proteoglycan concentration within the nucleus pulposus), thereby retarding the flow of nutrients into the disc as well as the flow of waste products out of the disc. This reduced capacity to eliminate waste may result in the accumulation of high levels of toxins which leads to nerve irritation and pain.
As DDD progresses, the toxic levels of the cytokines present in the nucleus pulposus begin to degrade the extracellular matrix. In particular, the MPPs (as mediated by the cytokines) begin cleaving the water-retaining portions of the proteoglycans, thereby reducing its water-retaining capabilities. This degradation leads to a less flexible nucleus pulposus, and so changes the loading pattern within the disc, thereby possibly causing delamination of the annulus fibrosus. These changes cause more mechanical instability, thereby causing the cells to emit even more cytokines, and thereby typically upregulating MMPs. As this destructive cascade continues and DDD further progresses, the disc begins to bulge (“a herniated disc”), and then ultimately ruptures, causing the nucleus pulposus to contact the spinal cord and produce pain.
Olmarker, Spine, 26(8): 863-9 (2001) (“Olmarker I”) and Aoki, Spine, 27(15): 1614-17 (2002) teach that TNF-α (TNF-alpha) appears to play a role in producing the pain associated with the nucleus pulposus contacting nerve roots of the spinal cord. Olmarker discourages the use of non-specific TNF-α inhibitors in spine-related drug therapies, and particularly those that have anti-biotic effects.
U.S. Published Patent Application No. U.S. 2003/0039651 (“Olmarker II”) teaches a therapeutic treatment of nerve disorders comprising administration of a therapeutically effective dosage of a number of drugs, including cycline compounds. According to Olmarker, tetracycline are non-specific inhibitors of TNF-α.
In the examples of Olmarker II, Olmarker II further teaches that these drugs are to be administered through systemic pathways. In particular, Olmarker II teaches that “the major contribution of TNF-α may be derived from recruited, aggregated and maybe even extravasated leukocytes, and that successful pharmacologic block may be achieved only by systemic treatment. Of note, Olmarker II appears to discourage the local addition of doxycycline to an autotransplanted nucleus pulposus to be applied to a spinal cord.
PCT Published Patent Application No. WO 02/100387 (“Olmarker III”) teaches the prevention of neovasculariation and/or neo-innervation of intervertebral discs by the administration of anti-angiogenic substances. Again, however, Olmarker III teaches systemic administration of these therapeutic agents.
U.S. Pat. No. 6,419,944 (“Tobinick”) discloses treating herniated discs with cytokine antagonists, including infliximab. However, Tobinick teaches that local administration involves a subcutaneous injection near the spinal cord. Accordingly, Tobinick does not teach a procedure involving a sustained delivery of a drug for the treatment of DDD, nor directly administering a cycline compound into the disc.
U.S. Published Patent Application No. 2003/0049256 (“Tobinick II”) discloses that injection of such therapeutic molecules to the anatomic area adjacent to the spine is accomplished by interspinous injection, and preferably is accomplished by injection through the skin in the anatomic area between two adjacent spinous processes of the vertebral column.
Tobinick, Swiss Med. Weekly, 133:170-77 (2003) (“Tobinick III”) teaches perispinal and epidural administration of specific TNF-α inhibitors.
Karppinen, Spine, 28(8): 750-4 (2003), teaches intravenously injecting or orally administering infliximab into patients suffering from sciatica.
As with Tobinick I and II, Karppinen does not teach a procedure involving a sustained delivery of a drug for the treatment of DDD, nor directly administering a cycline compound into the disc.
U.S. Pat. No. 6,352,557 (Ferree) teaches adding therapeutic substances such as anti-inflammatory medications to morselized extra-cellular matrix, and injecting that combination into an intervertebral disc.
Alini, Eur. Spine J., 11(Supp.2):S215-220 (2002) teaches therapies for early stage DDD, including injection of inhibitors of proteolytic enzymes or biological factors that stimulate cell metabolic activity (i.e., growth factors) in order to slow down the degenerative process. “Inhibitors of proteolytic enzymes” constitutes a broad class of compounds, including a) inhibitors of proteolytic enzyme synthesis and b) inhibitors of proteolytic enzyme activity.
U.S. Published Patent Application U.S. 2002/0026244 (“Trieu”) discloses an intervertebral disc nucleus comprising a hydrogel that may deliver desired pharmacological agents. Trieu teaches that these pharmacological agents may include growth factors such as TGF-β (TGF-beta) and anti-inflammatory drugs, including steroids. Trieu further teaches that these pharmacological agents may be dispersed within the hydrogel having an appropriate level of porosity to release the pharmacological agent at a desired rate. Trieu teaches that these agents may be released upon cyclic loading or upon resorption.
Goupille, Spine, 23(14): 1612-1626 (1998) identifies tetracycline as an inhibitor of MMP activity. However, Goupille also identifies corticosteroids, retinoic acid, TGF-β, PGE1 and PGE2 as inhibitors of MMP synthesis; identifies α2-macroglobulin, hydroxamic acid, derivatives, tetracycline and quinolones as inhibitors of MMP activity; and identifies bFGF, EGF, Retenoic acid, TGF-β, IL-6, IL-1 LIF, dexamethasone, phorbol ester, and synthetic Vitamin A analogs as stimulators of Tissue Inhibitors of metalloproteinases (“TIMPs”). Moreover, as to administration route, Goupille explicitly identifies only the oral administration route.
In sum, although investigators have generally taught the transdiscal administration of inhibitors of proteolytic enzymes, when investigators have specifically identified the administration of a cycline compound for spine-related therapy, the investigators appear to teach only the administration of the cycline compound to tissue outside the disc. Moreover, Olmarker II appears to discourage the administration of a cycline compound to a nucleus pulposus.